Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

Abstract

Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group. Conclusions Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

“…In fact, in patients affected by relapsed myeloma and treated with different BTZ regimens levels of proteasome inhibition ranging between 70 and 84% were measured after 1 cycle of treatment, and proteasomal activity recovered within 48 h from BTZ administration. 31 The prolonged proteasome inhibition observed in our study after 8 wk of treatment is substantially in agreement with the results of a preliminary study in multiple myeloma patients, where it was demonstrated that BTZ pharmacokinetic changes with repeated dose administration following reduction in plasma clearance and associated increase in systemic exposure. 32 This cumulative effect has not been completely explained so far, but it might be due to misfolded protein accumulation leading to "proteotoxic" event.…”

A Phase I Single-Agent Study of Twice-Weekly Consecutive-Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma

“…Clearance of carfilzomib occurred rapidly, and noncompartmental analysis revealed a mean elimination half-life of less than 30 minutes and no accumulation with repeat dosing. A more prolonged elimination half-life that seems to increase with repeat dosing has been reported for bortezomib, although similarly widespread tissue distribution has been observed (23). The V ss also mirrored observations in the 001 trial, again suggesting a wide tissue distribution (9).…”

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

“…In comparison, maximal whole blood CT‐L inhibition in several clinical studies with BTZ was reported to be 65–69% by either the intravenous or subcutaneous routes of administration on a twice‐weekly schedule (Cortes et al , 2004; Dy et al , 2005; Moreau et al , 2008), although sporadic individuals with up to 84% CT‐L reduction have been described (Reece et al , 2011). CFZ is a highly potent, irreversible and specific inhibitor of the CT‐L subunit (Kuhn et al , 2007) and, accordingly, was able to block 75% of CT‐L activity after one dose (O'Connor et al , 2009) in whole blood or PBMCs and up to 80–90% after repeat dosing (Alsina et al , 2012), although the most impressive activity was seen on an unapproved schedule of five daily doses (O'Connor et al , 2009).…”